UCH-L1-mediated Down-regulation of Estrogen Receptor α Contributes to Insensitivity to Endocrine Therapy for Breast Cancer

Chen, Xisha; Wang, Kuan-Song; Guo, Wei; Li, Lan-ya; Yu, Pei; Sun, Xinyuan; Wang, Haiyan; Guan, Yifu; Tao, Yongguang; Ding, Boni; Yin, Mingzhu; Ren, Xingcong; Zhang, Yi; Chen, Ceshi; Ye, Yuanchao; Yang, Jin‐Ming; Cheng, Yan

doi:10.7150/thno.39814

Cited by 31 publications

(48 citation statements)

References 59 publications

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“…In our previous study, we have reported that USP7, as a DUB, stabilizes ERα through removing ubiquitin on ERα 15 . A recent study has been reported a deubiquitnase UCHL1 conversely correlated with ERα, suggesting UCHL1 is not a DUB of ERα 16 . Hence, we are prompted to seek other DUBs of ERα.…”

Section: Introductionmentioning

confidence: 94%

The deubiquitinating enzyme USP15 stabilizes ERα and promotes breast cancer progression

et al. 2021

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Breast cancer has the highest incidence and mortality in women worldwide. There are 70% of breast cancers considered as estrogen receptor α (ERα) positive. Therefore, the ERα-targeted therapy has become one of the most effective solution for patients with breast cancer. Whereas a better understanding of ERα regulation is critical to shape evolutional treatments for breast cancer. By exploring the regulatory mechanisms of ERα at levels of post-translational modifications, we identified the deubiquitinase USP15 as a novel protector for preventing ERα degradation and a critical driver for breast cancer progression. Specifically, we demonstrated that USP15 promoted the proliferation of ERα+, but not ERα- breast cancer, in vivo and in vitro. Meanwhile, USP15 knockdown notably enhanced the antitumor activities of tamoxifen on breast cancer cells. Importantly, USP15 knockdown induced the downregulation of ERα protein via promoting its K48-linked ubiquitination, which is required for proliferative inhibition of breast cancer cells. These findings not only provide a novel treatment for overcoming resistance to endocrine therapy, but also represent a therapeutic strategy on ERα degradation by targeting USP15-ERα axis.

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Section: Introductionmentioning

confidence: 94%

The deubiquitinating enzyme USP15 stabilizes ERα and promotes breast cancer progression

et al. 2021

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“…Moreover, inactivation of neddylation with MLN4924 transcriptionally inhibits ERα and significantly improves the fulvestrant sensitivity 61 . However, in ER negative breast cancer, targeting ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1) upregulates ERα expression via enhancing ubiquitination and degradation of EGFR, and subsequently increases the sensitivity of tamoxifen and fulvestrant 62 .…”

Section: Drug Resistancementioning

confidence: 99%

Progress of Breast Cancer basic research in China

Wang

Guan

et al. 2021

Int. J. Biol. Sci.

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Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.

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“…Overexpression of EGFR is frequently observed in ER− breast cancer, which in turn hyperactivates mitogen-activated protein (MAP) kinase (MAPK) signalling [44][45][46], which may induce loss of ER gene transcription and expression [42,47], suggesting that UCHL1 regulates ER stability through EGFR stabilisation and subsequent MAPK hyperactivation. Finally, the authors showed that inhibiting or silencing UCHL1 can sensitise ER− cell lines to anti-estrogen therapy [41]. On the other hand, it has been reported that high expression of UCHL1 in TNBC cell lines facilitates cell invasion through activation of the Akt signalling pathway [48], and correlates with negative ER expression and overall shorter survival of breast cancer patients [49].…”

Section: Er Target Genesmentioning

confidence: 99%

UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology

et al. 2021

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Breast cancer has the highest incidence and death rate among cancers in women worldwide. In particular, metastatic estrogen receptor negative (ER–) breast cancer and triple-negative breast cancer (TNBC) subtypes have very limited treatment options, with low survival rates. Ubiquitin carboxyl terminal hydrolase L1 (UCHL1), a ubiquitin C-terminal hydrolase belonging to the deubiquitinase (DUB) family of enzymes, is highly expressed in these cancer types, and several key reports have revealed emerging and important roles for UCHL1 in breast cancer. However, selective and potent small-molecule UCHL1 inhibitors have been disclosed only very recently, alongside chemical biology approaches to detect regulated UHCL1 activity in cancer cells. These tools will enable novel insights into oncogenic mechanisms driven by UCHL1, and identification of substrate proteins deubiquitinated by UCHL1, with the ultimate goal of realising the potential of UCHL1 as a drug target in breast cancer.

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UCH-L1-mediated Down-regulation of Estrogen Receptor α Contributes to Insensitivity to Endocrine Therapy for Breast Cancer

Cited by 31 publications

References 59 publications

The deubiquitinating enzyme USP15 stabilizes ERα and promotes breast cancer progression

The deubiquitinating enzyme USP15 stabilizes ERα and promotes breast cancer progression

Progress of Breast Cancer basic research in China

UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology

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